Preparation method of hollow fiber dialysis membrane with precise gradient holes

Abstract

The invention discloses a preparation method of a hollow fiber dialysis membrane with precise gradient holes, which comprises the following steps: preparing a spinning solution and 0.1-0.5 wt% of sodium citrate core solution, injecting the spinning solution with the temperature of 50-54 DEG C and the core solution with the temperature of 40-44 DEG C into a spinning head to prepare a hollow fiber prototype, forming an initial fiber in an air section with the temperature of 36-40 DEG C, the RH of 60-70% and the diameter of 600-1000mm, and performing outer coagulating bath treatment at the temperature of 20-24 DEG C and inner coagulating bath treatment at the temperature of 40-44 DEG C to obtain the hollow fiber dialysis membrane with the precise gradient holes. And cleaning, drying, collecting and assembling after drafting. According to the method, the dialysis membrane with the inner diameter of 190-210 mu m, the wall thickness of 35-40 mu m, the inner surface aperture of 3-8 nm, the outer surface aperture of 50-200 nm and the radial aperture gradient larger than or equal to 4.5 nm / mu m is prepared by regulating and controlling parameters such as an air section and a coagulating bath, and the urea clearance rate gt is achieved. The albumin leakage rate is 1t; and the solute removal efficiency and the mechanical strength are balanced.

Description

Technical Field

[0001] The present invention belongs to the technical field of hemodialysis membranes, and in particular relates to a method for preparing a precise gradient pore hollow fiber dialysis membrane. Background Art

[0002] With the continuous advancement of medical technology, hemodialysis, as an important treatment for end-stage renal disease, has become increasingly widely used worldwide. In recent years, the number of dialysis patients has continued to grow, placing higher demands on the performance and quality of dialysis membranes. As a core component of hemodialysis equipment, the performance of dialysis membranes directly impacts dialysis effectiveness and patients' quality of life. In response to this development trend, the development of high-performance dialysis membranes has become a key research direction within the industry. Currently, dialysis membranes are evolving towards greater efficiency, safety, and biocompatibility. New materials and preparation processes are constantly emerging, aiming to enhance the dialysis membrane's ability to remove small molecule toxins while reducing the loss of macromolecules such as proteins, thereby better simulating the function of the human kidney. Furthermore, to improve the comfort and convenience of dialysis treatment, dialysis membranes are continuously being optimized in terms of mechanical strength and permeability to meet the diverse needs of different patient groups. These developments are driving continuous innovation in the dialysis membrane industry and promoting the advancement and iteration of related technologies.

[0003] Despite significant progress in dialysis membrane technology, practical applications still face numerous challenges. Among them, the conflict between small molecule clearance and protein retention is a key issue that urgently needs to be addressed. Existing dialysis membranes struggle to simultaneously achieve efficient small molecule toxin removal and precise protein retention, leading to nutrient loss or incomplete toxin removal during dialysis. For example, some dialysis membranes increase their pore size to improve small molecule clearance. However, this also makes it easier for important proteins like albumin to permeate the membrane, resulting in excessive albumin leakage, impacting patients' nutritional status and health. Meanwhile, some dialysis membranes designed to reduce protein leakage often perform poorly in small molecule clearance, failing to effectively remove small molecule toxins like urea, thus compromising dialysis effectiveness. Furthermore, the uniformity of the dialysis membrane's fiber structure and performance stability need to be improved. Differences in key parameters such as inner diameter, wall thickness, and pore size between different batches of dialysis membranes not only affect membrane quality consistency but can also lead to fluctuations in clinical treatment outcomes. Furthermore, over long-term use, dialysis membrane performance can be affected by a variety of factors, leading to degradation and inability to consistently and stably function, posing potential risks to patient treatment.

[0004] The dialysis membranes prepared in the Chinese invention patent application, "Method for Preparing Gradient-Structured Permanently Hydrophilic Polyethersulfone Hollow Fiber Membranes," with publication number CN115475536B, suffer from the aforementioned technical issues. This invention utilizes a specific polyethersulfone solution formulation and spinning process to prepare the dialysis membrane. However, based on the disclosure, it fails to fully consider the balance between small molecule clearance and protein retention through precise control of the membrane pore structure. The resulting membrane pore structure lacks precise control of pore size distribution and gradient. This makes it difficult to precisely control the permeation of proteins, such as albumin, while ensuring effective small molecule clearance in practical applications. This can result in high albumin leakage or insufficient small molecule clearance efficiency. Regarding fiber structure uniformity and performance stability, this prior art relies primarily on traditional spinning and post-processing processes, lacking advanced real-time monitoring and dynamic control systems. During the production process, key parameters such as spinning solution flow rate, temperature, and coagulation bath conditions cannot be adjusted in a timely manner, resulting in significant variations in membrane structural parameters such as inner diameter and wall thickness between different batches, impacting product quality consistency and stability. During long-term use, the performance of the membrane may fluctuate due to these inherent structural differences, making it difficult to continuously and stably meet clinical dialysis needs. Summary of the Invention

[0005] The object of the present invention is to provide a method for preparing a precision gradient pore hollow fiber dialysis membrane to solve the following technical problems raised in the background technology:

[0006] In the existing technology, it is difficult for dialysis membranes to simultaneously meet the requirements of high urea clearance and low albumin leakage rate, and there are problems such as uneven distribution of fiber inner diameter, wall thickness and pore size, and poor performance stability.

[0007] In order to solve the above technical problems, the technical solution adopted by the present invention is:

[0008] A method for preparing a precision gradient pore hollow fiber dialysis membrane comprises the following steps:

[0009] S1, prepare spinning solution and core solution;

[0010] Wherein, the core liquid is a 0.1-0.5wt% sodium citrate solution;

[0011] S2, injecting the spinning solution and the core solution into the spinning head to produce a hollow fiber prototype;

[0012] Among them, the spinning solution temperature is 50-54°C, and the core liquid temperature is 40-44°C;

[0013] S3, introducing the hollow fiber prototype into the air segment to form an initial fiber;

[0014] The environmental parameters of the air section are:

[0015] Temperature: 36-40℃;

[0016] Humidity: 60-70% RH;

[0017] Height: 600mm-1000mm;

[0018] S4, internal and external coagulation baths of the initial fibers;

[0019] Among them, the external coagulation bath is water or dimethylacetamide mixed solution, and the temperature is 20-24℃;

[0020] The inner coagulation bath is the core liquid, and the temperature is 40-44°C;

[0021] S5, drawing the initial fibers after the internal and external coagulation baths to obtain formed fibers;

[0022] S6, cleaning, drying and collecting the formed fibers, and assembling the formed fiber bundles to obtain a hollow fiber dialysis membrane.

[0023] Furthermore, the spinning solution is prepared as follows:

[0024] A, mixing polysulfone or polyethersulfone with polyvinylpyrrolidone and stirring for 20 minutes to form a mixture;

[0025] B. Slowly add dimethylacetamide to the mixture and stir at 70°C for 16 hours until the polymer is completely dissolved to form a polymer solution;

[0026] C, make the polymer solution flow downward along the wall of the kettle through the liquid guide pump, and maintain the vacuum degree ≤-0.095MPa;

[0027] D. The polymer solution is filtered through three stages of 20 μm, 10 μm, and 3 μm titanium alloy sintered filters to obtain the spinning solution.

[0028] Furthermore, the viscosity of the spinning solution is 3700±300 mPa.s.

[0029] Furthermore, the spinning solution temperature is preferably 52° C., the core solution temperature is preferably 42° C.; the inner diameter of the spinning head is Φ0.19 mm, and the annular gap is 90±5 μm.

[0030] Furthermore, the air section height is preferably 800 mm, the humidity is preferably 65% ​​RH, and the temperature is preferably 38°C.

[0031] Furthermore, the temperature of the outer coagulation bath is preferably 22°C, and the temperature of the inner coagulation bath is preferably 42°C.

[0032] Furthermore, the drawing speed is 10-20 m / min, preferably 15 m / min.

[0033] Furthermore, when drying the formed fiber, four different temperature stages are used for gradient drying, and the temperatures of each stage are 80°C, 90°C, 100°C and 90°C in sequence.

[0034] A precision gradient pore hollow fiber dialysis membrane is prepared using the method for preparing a precision gradient pore hollow fiber dialysis membrane described in the previous aspect, and the fiber structure parameters of the dialysis membrane are:

[0035] The inner diameter is 190-210 μm;

[0036] Wall thickness is 36-40 μm;

[0037] The inner surface pore size is 3-8nm;

[0038] The surface pore diameter is 50-200nm;

[0039] Radial pore gradient ≥4.5nm / μm.

[0040] A real-time monitoring system for real-time monitoring of a precision gradient pore hollow fiber dialysis membrane as described in the previous aspect, comprising a dual laser interferometer, an X-ray micro-focus scanning device, a small-angle laser scattering system, and a control system;

[0041] A dual laser interferometer is used to monitor the inner diameter of the molded fiber in real time; an X-ray micro-focus spot scanning device is used to monitor the wall thickness of the molded fiber in real time; and a small-angle laser scattering system is used to monitor the pore size distribution and gradient changes on the inner and outer surfaces.

[0042] Data from the laser diameter meter, X-ray micro-spot scanning device and small-angle laser scattering system are transmitted to the control system in real time. The control system automatically adjusts the spinning solution flow rate, drawing speed, air section height, core liquid temperature and sodium citrate concentration of the core liquid based on the real-time monitoring data.

[0043] Compared with the prior art, the present invention has the following beneficial effects:

[0044] The present invention uses a four-dimensional coordinated control system of an air segment, a coagulation bath, additives, and a monitoring system to achieve regulation of the dialysis membrane's inner diameter of 190-210 μm, a wall thickness of 35-40 μm, and a gradient pore structure of 3-8 nm / 50-200 nm on the inner and outer surfaces, achieving a urea clearance rate of >98% and an albumin leakage rate of <0.1 g / L, resolving the contradiction between small molecule clearance and protein retention. Furthermore, each process step is linked by parameters to ensure fiber structure uniformity and performance stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 It is a schematic diagram of the process of the present invention;

[0046] Figure 2 Schematic diagram of the physical electron microscope of the present invention. DETAILED DESCRIPTION

[0047] The following will provide a clear and complete description of the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts shall fall within the scope of protection of the present invention.

[0048] Example 1:

[0049] A method for preparing a precision gradient pore hollow fiber dialysis membrane, such as Figure 1 As shown, the following steps are included:

[0050] S1, prepare spinning solution and core solution;

[0051] Wherein, the preparation method of spinning solution is as follows:

[0052] A. 10-17 wt% polysulfone and 3-8 wt% polyvinylpyrrolidone are mixed and stirred for 20 minutes to form a mixture. The stirring and mixing uniformly disperses the polyvinylpyrrolidone in the polysulfone or polyethersulfone, improving the homogeneity of the polymer mixture. This helps to form a stable spinning solution during the subsequent dissolution process, avoiding spinning defects caused by uneven composition. Furthermore, the addition of polyvinylpyrrolidone can adjust the viscosity, fluidity, and other properties of the spinning solution to meet the spinnability requirements of the dry-jet-wet spinning process, ensuring the stability and continuity of the spinning process. For example, the solution viscosity is controlled within the appropriate range of 3700 ± 300 mPa·s.

[0053] B. Slowly add 75% to 87% dimethylacetamide by weight to the mixture and stir at 70°C for 16 hours until completely dissolved to form a polymer solution. Dimethylacetamide is a polar aprotic solvent with excellent solubility for polysulfone and polyvinylpyrrolidone. Heating at 70°C enhances molecular thermal mobility and reduces intermolecular interactions, such as hydrogen bonds and van der Waals forces. Combined with 16 hours of prolonged stirring, this promotes the full dispersion of polymer molecules in the dimethylacetamide, forming a uniform and stable spinning solution. The amount of dimethylacetamide added and the dissolution temperature directly affect the solution's viscosity, concentration, and thermodynamic compatibility. During the spinning stage, dimethylacetamide, as a solvent, gradually evaporates or is extracted, causing the polymer solution to undergo liquid-liquid phase separation, forming a "polymer-rich phase" and a "solvent-rich phase."

[0054] C. The polymer solution is made to flow downward along the wall of the kettle through a liquid guide pump and the vacuum degree is maintained at ≤-0.095MPa. The polymer solution is made to flow downward along the wall of the kettle through a liquid guide pump and the vacuum degree is maintained at ≤-0.095MPa. The bubbles in the solution can be efficiently removed with the help of the vacuum negative pressure. At the same time, the flow of the solution along the wall of the kettle can reduce the new bubbles generated by turbulence, ensuring that the spinning solution is free of bubbles, avoiding pore defects in the membrane filament, and providing stable raw materials for subsequent spinning forming.

[0055] D. The polymer solution is filtered through three stages of 20μm, 10μm, and 3μm titanium alloy sintered filters to produce a spinning solution. This three-stage filtration of the polymer solution through 20μm, 10μm, and 3μm titanium alloy sintered filters gradually removes undissolved particles, impurities, and gel blocks, preventing spinneret blockage or membrane pore defects. This ensures the purity of the spinning solution and the uniformity of the hollow fiber membrane's inner diameter, wall thickness, and pore structure, thereby improving the solute removal efficiency and mechanical strength of the dialysis membrane.

[0056] The synergistic effect of the polyvinyl pyrrolidone and dimethylacetamide mixed solvent system can alter the thermodynamic properties and phase separation behavior of the polymer solution. During the spinning process, this synergistic effect promotes more uniform liquid-liquid phase separation of the polymer solution, thereby precisely controlling the size, distribution, and connectivity of the membrane pores. This helps form a gradient pore design with a 3-8nm ultrafiltration layer on the inner surface and a 50-200nm macroporous structure on the outer surface, breaking the bottleneck of balancing solute removal efficiency and mechanical strength.

[0057] Among them, the viscosity of the spinning solution is controlled at 3700±300mPa.s, which can ensure that the solution has suitable fluidity and filamentation properties, avoid extrusion difficulties and fiber diameter fluctuations caused by too high viscosity, or breakage during stretching caused by too low viscosity, and lay the foundation for precise control of flow through metering pumps, stable extrusion of spinning heads, and subsequent closed-loop control of fiber inner diameter by laser diameter measuring instruments, thereby ensuring the molding quality and structural uniformity of hollow fiber membranes.

[0058] The core liquid adopts 0.1wt% sodium citrate solution; the use of 0.1wt% sodium citrate solution in the core liquid can reduce the phase separation rate constant k value, increase the diffusion coefficient D value with high-temperature core liquid, extend the phase separation time to a critical value in the air section, induce rapid phase separation on the inner surface to form a 3-8nm dense ultrafiltration layer, and at the same time avoid the dense layer being too thick to reduce the flux, realize the gradient pore structure of nanopores on the inner surface and macropores on the outer surface, and balance the solute removal efficiency and mechanical strength.

[0059] S2, injecting the spinning solution and the core solution into the spinning head to produce a hollow fiber prototype;

[0060] The spinning solution temperature is 50°C and the core solution temperature is 40°C.

[0061] The spinning dope temperature ensures optimal fluidity and filamentation. Typically, the spinning dope temperature is controlled between 50-54°C to avoid excessive viscosity and extrusion difficulties caused by low temperatures, or rapid solvent volatilization and polymer degradation caused by high temperatures. Furthermore, a temperature of 50-54°C precisely regulates the solvent volatilization rate in the air phase of the spinning dope, promoting the formation of a macroporous structure of 50-200 nm on the outer surface, providing a transport channel for the efficient removal of small molecule toxins. In this example, at a spinning dope temperature of 50°C, the outer surface pore diameter reached 182 nm, and the urea clearance rate exceeded 98%. If the temperature is lowered below 50°C, for example, to 45°C, the outer surface pore diameter decreases to 30-40 nm, causing the urea clearance rate to drop below 85%. If the temperature difference exceeds 14°C, the inner surface phase separation rate is too rapid, resulting in an excessively thick dense layer and reduced flux. While the urea clearance rate is high, the membrane permeability is reduced. If the temperature difference is <10°C, the phase separation rate on the inner surface slows down, the pore diameter of the nanopores increases to 8-15 nm, and the albumin leakage rate increases to above 0.3 g / L.

[0062] In this embodiment, a high-temperature core liquid containing 0.1-0.5 wt% sodium citrate in the spinning solution increases the diffusion coefficient of the polymer solution on the inner surface, accelerating the phase separation process and inducing the rapid formation of a dense ultrafiltration layer of 3-8 nm on the inner surface, thereby retaining macromolecules such as albumin. Furthermore, a temperature difference of 10-14°C between the core liquid and the spinning solution temperature ensures rapid phase separation and formation of nanopores on the inner surface, while macropores slowly form in the air region on the outer surface, achieving a radial pore gradient of ≥4.5 nm / μm.

[0063] The spinning head adopts a concentric spinning head with an inner diameter of 0.19 mm and an annular gap of 90±5 μm.

[0064] Through the concentric spinning head, the spinning liquid is squeezed out from the annular gap and the core liquid is injected from the central channel.

[0065] A concentric spinning head is used to control the spinning solution at 50°C and the core solution at 40°C, which are injected and extruded from the annular gap and the central channel. The temperature difference can be used to regulate the phase separation dynamics of the inner and outer surfaces.

[0066] The phase separation kinetic equation is as follows:

[0067]

[0068] Here, Φ is the polymer concentration, which characterizes the proportion of polymer in the solution and directly affects the formation of polymer-rich phase and solvent-rich phase during phase separation.

[0069] t is the time, which is used to measure the progress of the phase separation process.

[0070] D is the diffusion coefficient, which reflects the diffusion ability of polymer molecules in the solution. Its value is affected by factors such as the core liquid temperature and determines the rate of change of the concentration gradient.

[0071] is the Laplace operator of polymer concentration, which describes the spatial gradient of concentration distribution and reflects the evolution of concentration inhomogeneity during phase separation.

[0072] k is the phase separation rate constant, which controls the speed of phase separation. It can be reduced by 30% by adding sodium citrate to slow down the internal surface phase separation rate.

[0073] Φ0 is the initial polymer concentration, which serves as the benchmark value for the phase separation process. The difference between it and the current concentration φ affects the driving force for phase separation.

[0074] The high-temperature sodium citrate solution promotes rapid phase separation on the inner surface to form 3-8nm nanopores. The spinning solution evaporates the solvent in the air section to form 50-200nm macropores on the outer surface. At the same time, precise annular gap size and temperature control ensure the uniformity of the fiber inner diameter and wall thickness, realizing the formation of a gradient pore structure.

[0075] S3, introducing the hollow fiber prototype into the air segment to form an initial fiber;

[0076] The environmental parameters of the air section are:

[0077] Temperature: 35℃;

[0078] Humidity: 60% RH;

[0079] Height: 600mm;

[0080] In the air section, the solvent slowly evaporates and the polymer undergoes liquid-liquid phase separation. Initially, the outer surface of the fiber contacts the air, forming 50-200nm macropores, while the inner surface contacts the high-temperature core liquid, which rapidly separates into dense pores of 3-8nm.

[0081] S4, internal and external coagulation baths of the initial fibers;

[0082] The external coagulation bath is water or dimethylacetamide mixed solution, and the temperature is 20℃;

[0083] The internal coagulation bath is core liquid, and the temperature is 40°C;

[0084] It should be noted that the temperature of the inner and outer coagulation baths needs to be controlled at 16-24°C to coordinate with the air segment parameters to accurately control the wall thickness and pore size gradient.

[0085] If the temperature difference is greater than 24°C, the difference in curing rate between the inside and outside will be too large, which will lead to stress concentration in the fiber and a decrease in mechanical strength.

[0086] If the temperature difference is <16°C, the curing synergistic effect is weakened, the wall thickness fluctuation increases to ±5 μm, and the pore size gradient decreases to below 2.0 nm / μm.

[0087] The fiber is solidified and the 50-200nm macroporous structure on the outer surface is fixed by extracting the solvent in an external coagulation bath. The internal coagulation bath maintains a high temperature environment on the inner surface and continues to promote rapid phase separation on the inner surface to consolidate the 3-8nm dense pores. At the same time, the temperature difference between the internal and external coagulation baths cooperates with the air segment parameters to ensure precise control of the fiber inner diameter and wall thickness and stable molding of the gradient pore structure.

[0088] S5, drawing the initial fibers after the internal and external coagulation baths to obtain formed fibers;

[0089] Specifically, a drafting device applies a drafting force of 10 m / min to the initial fibers after internal and external coagulation baths. During the drafting process, the fiber diameter is monitored in real time, and the drafting speed is dynamically adjusted using a servo motor closed-loop control system to ensure uniform axial extension of the fibers while controlling the inner diameter and wall thickness. The drafting operation eliminates localized stress unevenness during fiber formation, improving the mechanical strength of the membrane filaments, such as a burst strength of >0.9 MPa. The stretching action further optimizes the orientation of the pore structure, laying the foundation for subsequent post-processing and ensuring stable dialysis performance.

[0090] S6, cleaning, drying and collecting the formed fibers, and assembling the formed fiber bundles to obtain a hollow fiber dialysis membrane.

[0091] Specifically, the formed fibers are placed in a cleaning device, and residual dimethylacetamide solvent is thoroughly removed by running water to prevent the residual solvent from affecting the biocompatibility and dialysis performance of the membrane; the cleaned fibers are then placed in a drying device for gradient temperature drying, first dried at 80°C for a period of time, then gradually heated to 90°C and 100°C, and finally cooled to 90°C to ensure that the moisture in the fibers evaporates slowly and evenly, and the final moisture content is controlled at ≤1% to prevent fiber deformation or internal stress caused by drying too quickly; after drying, the fibers are neatly rolled onto a special polygonal collection wheel to avoid fiber entanglement or stretching deformation, ensuring the integrity and uniformity of the fiber bundle; finally, the formed fiber bundle is assembled according to a specific process, including steps such as fixing the fiber bundle and sealing the ends, and finally a hollow fiber dialysis membrane with a specific inner diameter, wall thickness and gradient pore structure is obtained. The membrane can achieve urea clearance >98% and albumin leakage rate <0.1g / L, meeting the clinical needs of hemodialysis.

[0092] A real-time monitoring system for real-time monitoring of precision gradient pore hollow fiber dialysis membranes, comprising a dual laser interferometer, an X-ray micro-focus scanning device, a small-angle laser scattering system, and a control system;

[0093] A dual laser interferometer is used to monitor the inner diameter of the molded fiber in real time; an X-ray micro-focus spot scanning device is used to monitor the wall thickness of the molded fiber in real time; and a small-angle laser scattering system is used to monitor the pore size distribution and gradient changes on the inner and outer surfaces.

[0094] Specifically, the dual-laser interferometer emits two laser beams in real time with a measurement accuracy of ±0.5μm to perform radial scanning on the molded fiber. The inner diameter of the fiber is accurately calculated by the changes in the interference fringes, and can capture the ±15% deviation caused by drafting fluctuations. For example, the inner diameter fluctuation in traditional processes reaches 220±15μm, providing real-time data for inner diameter closed-loop control.

[0095] The X-ray micro-focus scanning device uses a micro-focus X-ray source to perform layered scanning on the fiber cross section with a resolution of 1μm. It monitors the uniformity of wall thickness in real time and can identify thin-walled areas, such as thickness fluctuations during 35μm gradient hole forming.

[0096] The low-angle laser scattering system irradiates the fiber surface with low-angle laser light and analyzes the pore size distribution and radial gradient change rate (≥4.5nm / μm) of the 3-8nm nanopores on the inner surface and the 50-200nm macropores on the outer surface in real time.

[0097] The three types of monitoring data are transmitted to the industrial control system at a frequency of milliseconds. The system is based on the phase dynamic equation. Establish a real-time control model:

[0098] When the inner diameter deviates from the 200μm threshold, the spinning solution metering pump flow rate and the drawing speed are automatically adjusted by ±5%, and the deviation is corrected through servo motor closed-loop control. The spinning solution flow rate directly affects the extrusion volume. When the flow rate is too large, the fiber diameter will expand. Reducing the flow rate can reduce the extrusion volume of the polymer solution per unit time, controlling the inner diameter expansion from the source. Increasing the drawing speed can increase the axial tensile force, so that the fiber is evenly stretched during the molding process, and the inner diameter shrinks accordingly. This operation needs to be linked with flow regulation to avoid fiber breakage caused by simply increasing the speed. Based on the phase separation kinetics equation, the adjustment of the flow rate and drawing speed can change the extrusion rate and tensile stress of the polymer solution, thereby affecting the radial shrinkage rate of the fiber during the phase separation process and achieving precise control of the inner diameter.

[0099] For example, if the measured inner diameter is 215 μm, exceeding the 200 μm threshold by +7.5%, the system automatically reduces the spinning solution metering pump flow by 5%, from the standard flow of 10 mL / min to 9.5 mL / min, and simultaneously increases the drafting speed to 18 m / min. Through closed-loop control of the servo motor, the inner diameter is reduced to 205 ± 3 μm, with a deviation correction rate of 93%.

[0100] If the wall thickness monitoring value exceeds the range of 35-40μm, the system will synchronously adjust the air section height and the external coagulation bath temperature to optimize the synergistic effect of the dual-temperature zone coagulation bath. Increasing the air section height can extend the residence time of the fiber in the air, promote solvent volatilization, reduce the fluidity of the polymer solution, and cause the fiber to shrink in advance before entering the coagulation bath, thereby reducing the wall thickness. Lowering the external coagulation bath temperature can accelerate the solvent extraction rate, allowing the outer surface of the fiber to solidify rapidly and limit the growth of wall thickness. The air section and the external coagulation bath can precisely control the phase separation dynamics to avoid uneven pore size distribution caused by single parameter adjustment. The solvent volatilization rate is positively correlated with the air section height, and the coagulation bath temperature is negatively correlated with the solidification rate. By linking the two, wall thickness optimization can be achieved without affecting the pore size gradient.

[0101] For example, when the wall thickness monitoring value is 42μm, exceeding the upper limit of 40μm, the system will simultaneously increase the air section height from 800mm to 850mm and reduce the external coagulation bath temperature from 22°C to 20°C, thereby strengthening the synergistic effect of the dual temperature zones and reducing the wall thickness to 38±1μm, with fluctuations controlled within ±1μm.

[0102] When the pore size gradient deviates from 4.5nm / μm, the core liquid temperature and sodium citrate concentration are automatically adjusted to ensure the formation of a gradient structure between the inner surface nanopores and the outer surface macropores by regulating the diffusion coefficient D and the phase separation rate constant k. Increasing the core liquid temperature can increase the diffusion coefficient, accelerate the phase separation of the inner surface polymer solution, and cause the inner surface pore size to decrease, thereby improving the radial gradient. Increasing the sodium citrate concentration can reduce the phase separation rate constant and slow down the inner surface phase separation rate. In combination with high-temperature core liquid, the formation of nanopores can be precisely controlled to avoid the dense layer being too thick and affecting the flux. According to the phase separation kinetic equation, the D value is exponentially related to the temperature, and the k value is linearly related to the additive concentration. The two can work together to achieve dynamic optimization of the pore size gradient.

[0103] For example, if the measured gradient is 4.0 nm / μm, which is lower than the threshold of 4.5 nm / μm, the system will raise the core liquid temperature from 40°C to 44°C, increase the diffusion coefficient D by 50%, and simultaneously increase the sodium citrate concentration from 0.1 wt% to 0.3 wt%, reduce the phase separation rate constant k by 30%, and reduce the inner surface pore size from 5.2 nm to 3.8 nm. The gradient is increased to 5.3 nm / μm, and the compliance rate is 118%.

[0104] The data from the laser diameter meter, X-ray micro-spot scanning device and small-angle laser scattering are transmitted to the control system in real time. The control system automatically adjusts the spinning solution flow rate, drawing speed, air section height, core liquid temperature and sodium citrate concentration of the core liquid according to the real-time monitoring data.

[0105] The electron microscope images of the objects obtained by the above steps are as follows: Figure 2 As shown. Among them, the pore size of the inner wall surface of the membrane is 5-8nm, for example Figure 2The width of the small rectangular box in the upper left corner. The pore size of the outer wall of the membrane is 100-200nm, for example Figure 2 The width of the large rectangular box in the lower right corner and the pore size are gradually increasing, reducing the resistance of molecules passing through the membrane.

[0106] The fiber structure parameters of the dialysis membrane prepared by the above steps are:

[0107] The inner diameter is 198 ± 4 μm;

[0108] Wall thickness is 36 ± 2 μm;

[0109] The inner surface pore diameter is 3.8 nm;

[0110] The surface pore diameter is 182nm;

[0111] Radial pore size gradient 5.3 nm / μm;

[0112] Urea clearance rate was 98%;

[0113] The albumin leakage rate was <0.1 g / L.

[0114] Example 2:

[0115] Different from Example 1, in this embodiment:

[0116] The core liquid is 0.25 wt% sodium citrate solution.

[0117] The environmental parameters of the air section are:

[0118] Temperature: 38°C

[0119] Humidity: 65% RH;

[0120] Height: 800mm.

[0121] The temperature of the outer coagulation bath was 22°C, the temperature of the inner coagulation bath was 42°C; and the drawing speed was 15 m / min.

[0122] The fiber structural parameters of the dialysis membrane prepared by the above steps are: inner diameter 205 ± 3 μm;

[0123] Wall thickness is 38 ± 1 μm;

[0124] The inner surface pore diameter is 5.2 nm;

[0125] The surface pore diameter is 155nm;

[0126] Radial pore size gradient 4.7 nm / μm;

[0127] Urea removal rate: 99%

[0128] Albumin leakage rate: <0.1g / L

[0129] Example 3:

[0130] Different from Example 1, in this embodiment:

[0131] The core liquid is 0.5 wt% sodium citrate solution.

[0132] The environmental parameters of the air section are:

[0133] Temperature: 40℃;

[0134] Humidity: 70% RH;

[0135] Height: 1000mm.

[0136] The temperature of the outer coagulation bath was 24°C, the temperature of the inner coagulation bath was 44°C; and the drawing speed was 20 m / min.

[0137] The fiber structural parameters of the dialysis membrane prepared by the above steps are: inner diameter 202 ± 5 μm;

[0138] Wall thickness is 35±2μm;

[0139] The inner surface pore size is 3.0 nm;

[0140] The surface pore diameter is 200nm;

[0141] Radial pore size gradient 6.0 nm / μm;

[0142] Urea clearance rate: 98.7%

[0143] Albumin leakage rate: <0.1g / L

[0144] Example 4:

[0145] Different from Example 1, in this embodiment:

[0146] The polyethersulfone and polyvinylpyrrolidone were mixed and stirred for 20 minutes to form a mixture.

[0147] The fiber structure parameters of the dialysis membrane prepared by the above steps are:

[0148] The inner diameter is 202 ± 3 μm;

[0149] Wall thickness is 37 ± 1 μm;

[0150] The inner surface pore size is 4.5 nm;

[0151] The surface pore diameter is 160nm;

[0152] Radial pore size gradient 4.9 nm / μm;

[0153] Urea clearance rate: 98.8%

[0154] Albumin leakage rate: <0.1g / L

[0155] Comparative Example 1:

[0156] Different from Example 1, in this embodiment, no gradient hole design is adopted, the core liquid is pure water, the air section height is 300 mm, and no temperature difference between the inner and outer coagulation baths is set.

[0157] The fiber structure parameters of the dialysis membrane prepared by the above steps are:

[0158] The inner diameter is 220 ± 15 μm;

[0159] Wall thickness is 45±5μm;

[0160] The inner surface pore size is 15 nm;

[0161] The surface pore diameter is 40nm;

[0162] Radial pore size gradient 0.8 nm / μm;

[0163] Urea clearance rate: 82%

[0164] Albumin leakage rate: 0.8g / L

[0165] Comparative Example 2:

[0166] Different from Example 1, this embodiment is not equipped with real-time monitoring systems such as dual laser interferometers, X-ray micro-focus scanning devices, and angular laser scattering systems, and parameter fluctuations are manually adjusted.

[0167] The fiber structure parameters of the dialysis membrane prepared by the above steps are:

[0168] The inner diameter is 210 ± 10 μm;

[0169] Wall thickness is 40±5μm;

[0170] The inner surface pore size is 10 nm;

[0171] The surface pore diameter is 80nm;

[0172] Radial pore size gradient 2.0 nm / μm;

[0173] Urea clearance rate: 90%

[0174] Albumin leakage rate: 0.3g / L.

[0175] The data comparison of each embodiment and comparative example is shown in Table 1:

[0176] Table 1

[0177]

[0178]

[0179] In each embodiment, the inner diameter is controlled at 198-205 μm, with a deviation of ≤±5 μm, and the wall thickness is 35-38 μm, reflecting the dimensional control capability of the precision spinning process and the real-time monitoring system.

[0180] In each embodiment, the inner surface pore diameter is 3.0-5.2 nm, the outer surface pore diameter is 155-200 nm, and the radial gradient is 4.7-6.0 nm / μm, which verifies the effectiveness of the gradient pore structure coordinated by the core liquid temperature, sodium citrate concentration and air segment parameters.

[0181] In each embodiment, the urea clearance rate is greater than 98% and the albumin leakage rate is less than 0.1 g / L, which meets the clinical needs of hemodialysis and is significantly improved compared to traditional processes.

[0182] In Comparative Example 1, the gradient pore design was not adopted. The inner surface pore diameter was too large, resulting in a high albumin leakage rate, and the outer surface pore diameter was too small, affecting the urea clearance rate, verifying the key role of the gradient pore structure in the solute separation selectivity.

[0183] In Comparative Example 2, when there is no real-time monitoring system, the inner diameter deviation increases to ±10 μm, the wall thickness fluctuates to ±5 μm, and the pore size gradient is only 2.0 nm / μm. The performance is between that of the embodiment and Comparative Example 1, indicating the decisive influence of dynamic control on parameter stability.

[0184] Each embodiment achieves a pore gradient of ≥4.5 nm / μm through a four-dimensional coordinated control system of an air section, a coagulation bath, additives, and a monitoring system, breaking through the contradiction between solute removal and mechanical strength in traditional processes.

[0185] Comparative Example 3:

[0186] The difference between this comparative example and Example 1 is that the spinning solution temperature is raised to 58° C. This temperature exceeds the range of 50-54° C. defined in Claim 1 and is intended to observe the situation when the spinning solution temperature is too high.

[0187] Obtained by this comparative example, the spinning solution temperature is too high, causing it to evaporate too quickly in the air section solvent, and the surface pore diameter is abnormally increased and distributed extremely unevenly. By scanning electron microscopy, the surface pore diameter can reach 300-500nm, which is significantly changed compared to the 182nm of Example 1. Although the urea clearance rate increases in the early stage due to the increase in pore size, the albumin leakage rate sharply increases to more than 0.5g / L due to the destruction of the screening function of the membrane by the macroporous structure, far exceeding the clinical acceptable range (<0.1g / L). At the same time, the rapidly evaporating solvent concentrates stress inside the fiber, and the mechanical strength decreases, and the burst strength is reduced to less than 0.7MPa, which is much lower than the 0.9MPa standard of Example 1.

[0188] The fiber structure parameters of the dialysis membrane prepared by the above steps are:

[0189] The inner diameter is 230 ± 18 μm;

[0190] Wall thickness is 48 ± 6 μm;

[0191] The inner surface pore size is 18 nm;

[0192] The surface pore diameter is 280nm;

[0193] Radial pore size gradient 1.5 nm / μm;

[0194] Urea clearance rate: 93%

[0195] Albumin leakage rate: 0.5g / L.

[0196] Comparative Example 4:

[0197] The difference between this comparative example and Example 1 is that the core liquid temperature is lowered to 35° C. to explore the impact of too low a core liquid temperature.

[0198] This comparative example demonstrates that excessively low core fluid temperature significantly reduces the diffusion coefficient of the inner surface polymer solution, slowing the phase separation process. The inner surface pore size increases to 12-15 nm, preventing the effective formation of a dense ultrafiltration layer. Dialysis performance also increases the albumin leakage rate to 0.3-0.4 g / L; urea clearance is also affected, falling to 92-94%, failing to meet the requirements for efficient removal of small molecule toxins. This demonstrates that core fluid temperature is crucial for forming an ideal inner surface nanopore structure; excessively low temperatures disrupt the equilibrium of the gradient pore structure.

[0199] The fiber structure parameters of the dialysis membrane prepared by the above steps are:

[0200] The inner diameter is 215 ± 12 μm;

[0201] Wall thickness is 42 ± 4 μm;

[0202] The inner surface pore size is 12 nm;

[0203] The surface pore diameter is 160nm;

[0204] Radial pore size gradient 2.8 nm / μm;

[0205] Urea clearance rate: 93%

[0206] Albumin leakage rate: 0.35g / L.

[0207] Comparative Example 5:

[0208] This comparative example differs from Example 1 in that the temperature of the external coagulation bath is increased to 28° C., and the effects of excessively high external coagulation bath temperature are compared and studied.

[0209] Through this comparative example, it was found that when the temperature of the external coagulation bath is too high, the solvent extraction rate is too fast, and the curing process of the outer surface of the fiber is difficult to accurately control. The pore diameter of the outer surface becomes irregular, and the pore diameter in some areas exceeds 250nm. The wall thickness fluctuation intensifies, reaching 45-50μm, exceeding the standard range of 35-40μm. This structural change leads to a decrease in the solute removal efficiency and mechanical strength of the dialysis membrane. The urea clearance rate drops to about 90%, and the albumin leakage rate increases to 0.2-0.3g / L. At the same time, the burst strength of the membrane is reduced to about 0.8MPa, affecting the service life and safety of the dialysis membrane.

[0210] The fiber structure parameters of the dialysis membrane prepared by the above steps are:

[0211] The inner diameter is 225 ± 16 μm;

[0212] Wall thickness is 46 ± 5 μm;

[0213] The inner surface pore size is 16 nm;

[0214] The surface pore diameter is 260nm;

[0215] Radial pore size gradient 1.8 nm / μm;

[0216] Urea clearance rate: 91%

[0217] Albumin leakage rate: 0.25g / L.

[0218] Comparative Example 6:

[0219] The difference between this comparative example and Example 1 is that the temperature of the internal coagulation bath in this comparative example is lowered to 35°C.

[0220] Through this comparative example, it was found that the temperature of the inner coagulation bath was too low to continuously provide a suitable environment for the inner surface phase separation, resulting in insufficient inner surface phase separation. The inner surface pore size increased to 10-12nm, and the radial pore size gradient decreased to 2.5-3.0nm / μm, which is far below the requirement of ≥4.5nm / μm. In terms of dialysis performance, the urea clearance rate dropped to 93-95%, and the albumin leakage rate increased to 0.25-0.35g / L, indicating that the inner coagulation bath temperature is indispensable for maintaining the stability of the inner surface nanopore structure and gradient pores. Too low a temperature destroys the key performance indicators of the dialysis membrane.

[0221] The fiber structure parameters of the dialysis membrane prepared by the above steps are:

[0222] The inner diameter is 212 ± 10 μm;

[0223] Wall thickness is 41 ± 4 μm;

[0224] The inner surface pore size is 10 nm;

[0225] The surface pore diameter is 170nm;

[0226] Radial pore size gradient 3.0 nm / μm;

[0227] Urea clearance rate: 94%

[0228] Albumin leakage rate: 0.3g / L.

[0229] The data comparison of Example 1, Example 2, Example 3, Comparative Example 3, Comparative Example 4, Comparative Example 5 and Comparative Example 6 is shown in Table 2:

[0230] Table 2

[0231]

[0232]

[0233] By comparing the data in Table 2, it can be seen that in the embodiment, when the spinning solution temperature parameters are within the range of 50-54°C, the core liquid temperature is controlled at 40-44°C, and the external coagulation bath temperature is controlled at 20-24°C, the phase separation dynamics can be precisely controlled to form a gradient structure with a 3-8nm ultrafiltration layer on the inner surface and 50-200nm macropores on the outer surface, thereby achieving a balance between solute removal and protein retention. If the spinning solution temperature exceeds the upper limit, the uniformity of the surface pore structure will be destroyed, resulting in a protein leakage rate that soars by more than 5 times. If the core temperature is lower than the lower limit, it will directly lead to the failure of the nanopores on the inner surface, and the albumin leakage rate will exceed the clinical standard by 3 times. If the external coagulation bath temperature exceeds the upper limit, the wall thickness will be out of control, and the solute removal efficiency will drop by more than 7%.

[0234] In the embodiment, the temperature parameters are linked with the air section height, drawing speed, etc. to ensure that the inner diameter and wall thickness deviations are ≤±5μm. In the comparative example, a single temperature anomaly causes the fluctuation amplitude of the structural parameters to increase by 3-4 times, verifying the necessity of the four-dimensional collaborative control system.

[0235] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing a precision gradient pore hollow fiber dialysis membrane, characterized in that: The following steps are involved: S1, prepare spinning solution and core solution; Wherein, the core liquid is a 0.1-0.5wt% sodium citrate solution; S2, injecting the spinning solution and the core solution into the spinning head to produce a hollow fiber prototype; Among them, the spinning solution temperature is 50-54°C, and the core liquid temperature is 40-44°C; S3, introducing the hollow fiber prototype into the air segment to form an initial fiber; The environmental parameters of the air section are: Temperature: 36-40℃; Humidity: 60-70% RH; Height: 600mm-1000mm; S4, internal and external coagulation baths of the initial fibers; Among them, the external coagulation bath is water or dimethylacetamide mixed solution, and the temperature is 20-24℃; The inner coagulation bath is the core liquid, and the temperature is 40-44°C; S5, drawing the initial fibers after the internal and external coagulation baths to obtain formed fibers; S6, cleaning, drying and collecting the formed fibers, and assembling the formed fiber bundles to obtain a hollow fiber dialysis membrane.

2. The method for preparing a precision gradient pore hollow fiber dialysis membrane according to claim 1, characterized in that: The preparation method of the spinning solution is as follows: A, mixing polysulfone or polyethersulfone with polyvinylpyrrolidone and stirring for 20 minutes to form a mixture; B. Slowly add dimethylacetamide to the mixture and stir at 70°C for 16 hours until the polymer is completely dissolved to form a polymer solution; C, make the polymer solution flow downward along the wall of the kettle through the liquid guide pump, and maintain the vacuum degree ≤-0.095MPa; D. The polymer solution is filtered through three stages of 20 μm, 10 μm, and 3 μm titanium alloy sintered filters to obtain the spinning solution.

3. The method for preparing a precision gradient pore hollow fiber dialysis membrane according to claim 2, wherein: The viscosity of the spinning solution is 3700±300 mPa.s.

4. The method for preparing a precision gradient pore hollow fiber dialysis membrane according to claim 1, wherein: The spinning solution temperature is preferably 52° C., the core solution temperature is preferably 42° C.; the inner diameter of the spinning head is Φ0.19 mm, and the annular gap is 90±5 μm.

5. The method for preparing a precision gradient pore hollow fiber dialysis membrane according to claim 1, wherein: The air section height is preferably 800 mm, the humidity is preferably 65% ​​RH, and the temperature is preferably 38°C.

6. The method for preparing a precision gradient pore hollow fiber dialysis membrane according to claim 1, characterized in that: The temperature of the outer coagulation bath is preferably 22°C, and the temperature of the inner coagulation bath is preferably 42°C.

7. The method for preparing a precision gradient pore hollow fiber dialysis membrane according to claim 1, characterized in that: The drawing speed is 10-20 m / min, preferably 15 m / min.

8. The method for preparing a precision gradient pore hollow fiber dialysis membrane according to claim 1, characterized in that: When drying the formed fiber, four different temperature stages are used for gradient drying, and the temperatures of each stage are 80℃, 90℃, 100℃ and 90℃ respectively.

9. A precision gradient pore hollow fiber dialysis membrane, prepared using the method for preparing a precision gradient pore hollow fiber dialysis membrane according to any one of claims 1 to 8, characterized in that: The fiber structure parameters of the dialysis membrane are: The inner diameter is 190-210 μm; Wall thickness is 36-40 μm; The inner surface pore size is 3-8nm; The surface pore diameter is 50-200nm; Radial pore gradient ≥4.5nm / μm.

10. A real-time monitoring system for real-time monitoring of the precision gradient pore hollow fiber dialysis membrane according to claim 9, characterized in that: It includes dual laser interferometers, X-ray micro-focus scanning device, small-angle laser scattering system and control system; Use dual laser interferometers to monitor the inner diameter of the molded fiber in real time; use an X-ray micro-focus scanning device to monitor the wall thickness of the molded fiber in real time; use small-angle laser scattering to monitor the pore size distribution and gradient changes on the inner and outer surfaces; Data from the laser diameter meter, X-ray micro-spot scanning device and small-angle laser scattering system are transmitted to the control system in real time. The control system automatically adjusts the spinning solution flow rate, drawing speed, air section height, core liquid temperature and sodium citrate concentration of the core liquid based on the real-time monitoring data.

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